The opioidergic system, including kappa (KOR) and delta (DOR) opioid receptors, plays a major role in the body's ability to respond to cognitive and non-cognitive stimuli. Signal transduction systems that mediate the cellular actions of KOR and DOR activation include: adenylyl cyclase, K and Ca channels, mitogen-activated protein kinase and phospholipases C and A. Research from this laboratory has demonstrated that naturally occurring and synthetic agents that stimulate KOR and DOR can produce significant effects on ocular hydrodynamics, such as lowering intraocular pressure and suppressing the rate of aqueous humor flow. Results from studies performed in subhuman primates support the suggestion that KOR have a role in modulating ocular hydrodynamics. Immunohistochemical identification of KOR and their related G (GTP)-binding proteins in human trabecular meshwork cells and neuroendocrinological (elevation of natriuretic peptide levels) evidence in rabbits support the supposition that KOR agonists should have effects that enhance outflow facility. The proposed study will examine the hypothesis that opioidergic systems modulate hydrodynamics and produce cytoprotective actions in the eye by direct and indirect mechanisms. This hypothesis will be tested by: 1) evaluating the involvement of neuroendocrine systems that mediate the indirect ocular hydrodynamic actions of KOR and DOR agonists; 2) determining the ocular sites and dynamics of KOR and DOR that modulate aqueous humor inflow and outflow; 3) elucidating the interactions among signal transduction mechanisms linked to DOR and KOR that mediate the ocular hydrodynamic actions of opioidergic agonists; 4) ascertaining the site(s) and mechanism(s) by which DOR and KOR agonists produce ocular neuroprotection. Experiments will be conducted at the organ, tissue and cellular levels in order to advance knowledge of the opioidergic systems in the eye. The elucidation of novel mechanisms involving DOR and KOR should have utility in: 1) improving the understanding of the endogenous modulation of aqueous humor dynamics and neuroprotection and 2) enabling the discovery of more efficacious therapies for glaucoma.